History

A 4-year-old 4.52-kg spayed female domestic shorthair cat was presented to the Louisiana State University Veterinary Teaching Hospital for evaluation of lethargy, abdominal effusion, and an abdominal mass. The cat was presented to her referring veterinarian 2 days earlier for vomiting and constipation where the abdominal mass and a fluid wave were noticed on physical examination. A CBC, biochemical analyses, and abdominal radiography were performed by the referring veterinarian. Results of the CBC and biochemical analyses revealed neutrophilic leukocytosis and high activities of a γ-glutamyltransferase (Table 1). Abdominal radiography revealed substantial loss of serosal detail from peritoneal effusion and a cranial abdominal mass (not shown).

Clinical and Clinicopathologic Findings

On physical examination, clinically important findings included a markedly distended abdomen with a palpable fluid wave and abdominal discomfort. Thoracic radiographs revealed severe abdominal effusion with severe hepatomegaly and a cavitated pulmonary mass in the right caudal lung lobe. Abdominal ultrasonography revealed a large amount of mildly echoic abdominal effusion. In addition, approximately 75% of the liver was effaced with multiple masses of variable size and echogenicity. Several of the masses had cavitated centers. The gastrointestinal tract had no apparent masses noted throughout the entire length. The pancreas and adrenal glands were normal. Abdominal fluid analysis was performed, which showed 80,000 RBCs/µL, 1,600 nucleated cells/µL, and a protein concentration of 4.0 g/dL with the interpretation of protein-enriched transudate versus low-grade neutrophilic inflammation. A feline infectious peritonitis PCR assay (FIP Virus RealPCR Test, Idexx Laboratories Inc) was performed on the abdominal fluid, and results were negative. A fine-needle aspirate was taken of multiple liver masses. The cytology showed necrosis with scattered epithelial cells, but a definitive diagnosis was not made. Therefore, liver biopsy was recommended.

The patient was presented for ultrasound-guided liver biopsy. The cat’s PCV was 25%, and coagulation parameters were within the reference interval prior to the biopsy. The biopsy (Tru-Cut, Merit Medical Systems; 16-gauge, 1.5-cm throw) was performed under general anesthesia without complication. This tissue was submitted for histopathologic review (Magnum biopsy instrument, Bard Medical).

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Histopathologic Findings

Multiple biopsy specimens were submitted in 10% formalin from separate lesions throughout the liver. Tissue samples were routinely processed for H&E staining and immunohistochemistry (Figure 1). All specimens were composed of > 90%, densely cellular, neoplastic cells. The neoplastic cells predominantly formed small packets and clusters surrounded by thin fibrovascular stroma with scattered rosettes, ducts, and tubules. The cells had minimal amounts of eosinophilic cytoplasm and indistinct cell margins. Nuclei were round to long oval and had dispersed chromatin with single, central to multiple nucleoli. The mitotic rate was 13 mitotic figures/10 hpfs. Scattered foci of squamous metaplasia were present.

Photomicrographs of liver tissue sections (obtained with the use of ultrasound-guided biopsy needle) from a 4-year-old 4.52-kg spayed female domestic shorthair cat evaluated because of lethargy, abdominal effusion, and an abdominal mass. A—The mass is composed of densely packed epithelial cells with minimal cytoplasm and often divided into packets by a delicate, fibrovascular stroma (arrows). H&E stain; bar = 50 µm. B—Chromogranin A (intense, reddish-brown staining) is detected in the cytoplasm of essentially all tumor cells. Immunohistochemical staining for chromogranin A (Polyclonal rabbit A0430, Agilent Technologies); bar = 50 µm. C—Neuron-specific enolase is evident with moderate to intense staining of the cytoplasm of essentially all tumor cells. Immunohistochemical staining for neuron-specific enolase (Monoclonal mouse M0873, Agilent Technologies); bar = 50 µm. D—Detection of synaptophysin is evident with mild to moderate cytoplasmic staining (arrows) of a portion of the tumor cells. Immunohistochemical staining for synaptophysin (Monoclonal mouse ab8049, Abcam); bar = 50 µm. E—Cytoplasmic cytokeratin-7 is evident in cells along this tubule-like structure (arrow). Immunohistochemical staining for cytokeratin 7 (Monoclonal mouse CM061, Biocare Medical); 50 µm. F—Approximately 37% of the cells have Ki-67 expression. Immunohistochemical staining for Ki-67 (Monoclonal mouse M7240, Dako); bar = 50 µm.

Citation: Journal of the American Veterinary Medical Association 259, S2; 10.2460/javma.20.03.0104

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Photomicrographs of liver tissue sections (obtained with the use of ultrasound-guided biopsy needle) from a 4-year-old 4.52-kg spayed female domestic shorthair cat evaluated because of lethargy, abdominal effusion, and an abdominal mass. A—The mass is composed of densely packed epithelial cells with minimal cytoplasm and often divided into packets by a delicate, fibrovascular stroma (arrows). H&E stain; bar = 50 µm. B—Chromogranin A (intense, reddish-brown staining) is detected in the cytoplasm of essentially all tumor cells. Immunohistochemical staining for chromogranin A (Polyclonal rabbit A0430, Agilent Technologies); bar = 50 µm. C—Neuron-specific enolase is evident with moderate to intense staining of the cytoplasm of essentially all tumor cells. Immunohistochemical staining for neuron-specific enolase (Monoclonal mouse M0873, Agilent Technologies); bar = 50 µm. D—Detection of synaptophysin is evident with mild to moderate cytoplasmic staining (arrows) of a portion of the tumor cells. Immunohistochemical staining for synaptophysin (Monoclonal mouse ab8049, Abcam); bar = 50 µm. E—Cytoplasmic cytokeratin-7 is evident in cells along this tubule-like structure (arrow). Immunohistochemical staining for cytokeratin 7 (Monoclonal mouse CM061, Biocare Medical); 50 µm. F—Approximately 37% of the cells have Ki-67 expression. Immunohistochemical staining for Ki-67 (Monoclonal mouse M7240, Dako); bar = 50 µm.

Citation: Journal of the American Veterinary Medical Association 259, S2; 10.2460/javma.20.03.0104

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Photomicrographs of liver tissue sections (obtained with the use of ultrasound-guided biopsy needle) from a 4-year-old 4.52-kg spayed female domestic shorthair cat evaluated because of lethargy, abdominal effusion, and an abdominal mass. A—The mass is composed of densely packed epithelial cells with minimal cytoplasm and often divided into packets by a delicate, fibrovascular stroma (arrows). H&E stain; bar = 50 µm. B—Chromogranin A (intense, reddish-brown staining) is detected in the cytoplasm of essentially all tumor cells. Immunohistochemical staining for chromogranin A (Polyclonal rabbit A0430, Agilent Technologies); bar = 50 µm. C—Neuron-specific enolase is evident with moderate to intense staining of the cytoplasm of essentially all tumor cells. Immunohistochemical staining for neuron-specific enolase (Monoclonal mouse M0873, Agilent Technologies); bar = 50 µm. D—Detection of synaptophysin is evident with mild to moderate cytoplasmic staining (arrows) of a portion of the tumor cells. Immunohistochemical staining for synaptophysin (Monoclonal mouse ab8049, Abcam); bar = 50 µm. E—Cytoplasmic cytokeratin-7 is evident in cells along this tubule-like structure (arrow). Immunohistochemical staining for cytokeratin 7 (Monoclonal mouse CM061, Biocare Medical); 50 µm. F—Approximately 37% of the cells have Ki-67 expression. Immunohistochemical staining for Ki-67 (Monoclonal mouse M7240, Dako); bar = 50 µm.

Citation: Journal of the American Veterinary Medical Association 259, S2; 10.2460/javma.20.03.0104

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Immunohistochemical staining to differentiate different neuroendocrine tumors was performed. Chromogranin A yielded intense, diffuse cytoplasmic staining (Polyclonal rabbit A0430, Agilent Technologies) of nearly all the neoplastic cells. Similarly, nearly all of the neoplastic cells had strong, diffuse cytoplasmic staining with neuron-specific enolase (NSE; Monoclonal mouse M0873, Agilent Technologies). Scattered tubular structures, especially those within or adjacent to fibrotic areas, had moderate apical cytoplasmic staining with cytokeratin-7 (Monoclonal mouse CM061, Biocare Medical). All of the cells growing in sheets and a slight majority of the tubular structures did not react with cytokeratin-7. The neoplastic cells were weakly positive for synaptophysin (Monoclonal mouse ab8049, Abcam), and staining for Ki-67 (Monoclonal mouse M7240, Dako) showed 37.2% positive cells from 400 cells over 2 different regions.

Morphologic Diagnosis and Case Summary

Morphologic diagnosis and case summary: hepatobiliary neuroendocrine carcinoma in a cat with potential lung metastasis.

Comments

Due to the extensive nature of this neoplasm, surgery was not considered a viable option in this case. A suspected pulmonary metastasis was identified on thoracic radiographs, although this was not confirmed by histology. Pulmonary metastasis has been reported previously in cats with hepatobiliary neuroendocrine tumors.¹ The peritoneal effusion was presumed to be secondary to hepatic portal hypertension caused by neoplastic effacement of normal hepatic architecture, although posthepatic venous obstruction or a neoplastic effusion cannot be ruled out. Treatment with toceranib phosphate 15 mg (3.2 mg/kg, PO, Monday, Thursday) and prednisolone 5 mg (1mg/kg, PO, q 24 h) was initiated after diagnosis. Two weeks later the cat was returned because of progressively lethargy, and its PCV had dropped to 20% with no evidence of regeneration. The patient’s toceranib phosphate dose was decreased to 10 mg (2.3 mg/kg, PO, Monday, Thursday). The cat was returned to the hospital 1 month after diagnosis minimally responsive and died in the hospital. A necropsy was not performed.

Nonlymphoid hepatic neoplasms in cats are rare and are estimated to account for about 2% of all feline neoplasms.¹ Van Sprundel et al² found that up to 13% (8/61) of primary liver tumors in cats were neuroendocrine tumors. Hepatic neuroendocrine tumors (previously termed carcinoids) are thought to arise from the neuroendocrine cells throughout the biliary system.^3,4 Neuroendocrine tumors of the liver can be divided into small cell carcinomas with hepatocellular progenitor cell characteristics and neuroendocrine carcinomas based on their staining with cytokeratin-19.² Clinical signs in cats typically include weight loss and anorexia if they are intrahepatic and icterus if the biliary tree is involved. In most species, the most common intrahepatic and extrahepatic bile ducts are equally common in cats.^1,4

The prognosis of cats with hepatic neuroendocrine tumors has not been thoroughly investigated, reported survival times range from 55 days to 11 months.^5,6 In humans, the mitotic count and Ki-67 index are included in the neuroendocrine tumor grading system as prognostic markers.⁷ Application of these indices as prognostic markers may be valuable in feline hepatobiliary neuroendocrine tumors as well. Our patient survived 39 days from initial presentation with toceranib phosphate treatment. The advanced stage of cancer likely shortened survival time in our patient. In human medicine, the standard of care for hepatic neuroendocrine tumors is surgical resection.⁸ Octreotide, systemic chemotherapy, or transarterial chemoembolization is an alternative treatment option if they are not surgically resectable.⁸ Nonlymphoid neoplasms of the liver are rare in cats, but tumors of hepatic and neuroendocrine origin should be considered as differential diagnoses in cats with hepatic masses.